Aging is not a uniform process among individuals. There are persons who rapidly develop age-related kidney disease, cardiovascular disease, frailty and anemia. The underlying cause(s) of age-related kidney disease are not clear, but glomerulosclerosis is a common pathological finding. A state of chronic inflammation characterized by increased circulating tumor necrosis factor a (TNF-a), interleukin 6 and c-reactive protein is usually present in those with rapid aging. We hypothesize that increased TNF-a is an important underlying cause of kidney disease in this rapidly aging subset. We use postmenopausal C57BL6 (B6) mice as a model of kidney disease in rapidly aging women. In this model, glomerular aging is a slowly progressive process that is accelerated by intercurrent injury. Postmenopausal B6 mice have increased serum TNF-a levels and phenotypic changes in glomerular cells rendering them more sensitive to TNF-a. Since B6 females lacking TNF receptor 1 (TNFR1) are largely protected from glomerular aging, we postulate that increased TNF-a in aging contributes significantly to progressive, or unresolved glomerular injury leading to glomerulosclerosis. In this proposal, we will first examine if systemic reduction of TNF-a slows the progression of glomerulosclerosis and improves glomerular injury resolution in aging. Second, we will examine the mechanism by which TNF-a induces the development and progression of glomerular aging by using mice which overexpress or lack TNF-a and its receptors. Thirdly, we will examine the mechanism by which TNF-a induces NF-kB activation in postmenopausal glomeruli and the pathway by which it operates in glomerular aging. To further explore the mechanism(s) for increased sensitivity of aging glomerular cells to TNF-a induced NF-kB activation, we will examine the classical pathway of TNF-a to NF-kB signaling by using glomerular cells isolated from knockout mice in which selected components in the pathway have been deleted. Since 11% of US population over the age of 60 has reduced renal function in the absence of obvious disease such as diabetes and hypertension, it is critical to elucidate the underlying cause and molecular mechanisms of age related chronic kidney disease. This proposal will attempt to identify factor(s) contributing to the development and progression of glomerulosclerosis in aging. [unreadable] [unreadable]